The goal of this project is to identify genetic risk factors for lung-involved sarcoidosis, a granulomatous interstitial lung disease (gILD). Lung-involved sarcoidosis results from an aberrant adaptive immune response to unknown antigenic stimuli. The prevalence of sarcoidosis is estimated to be between 10 and 35 per 100,000 in the United States, affecting people of all races, both genders and all ages. In some individuals, the immune response resolves with no long-term effects while in others there is severe lung impairment. We do not understand the mechanisms of granulomatous disease initiation nor why disease resolves in some individuals but progresses to severe disease, often resulting in death, in others. The mortality rate of sarcoidosis is increasing for reasons we also don't understand. Both genetic and environmental factors are important for determining sarcoidosis risk and the impact of environmental exposures on disease risk and severity likely differs depending on genetic factors. There is good evidence for the importance of immune-related genetic variants in sarcoidosis, although the specific immune-related variants and other genetic determinants of risk remain largely unidentified. Cigarette smoking is protective for sarcoidosis, but protection differs greatly among those with similar smoking histories. The central hypothesis of this proposal is that genetic variants in the major histocompatibility complex (MHC) play a primary role in the initiation of sarcoidosis by modulating antigen stimulation and that these variants, in addition to others, drive the initiation and perpetuation of granulomatous inflammation and ultimately disease severity. This project will identify genetic variants associated with lung- involved sarcoidosis by comparing cases with sarcoidosis to controls using both targeted examination of the MHC and agnostic screening of the genome via the HumanOmni2.5 BeadChip. To do so, this project will examine the most powerful discovery sample studied to date, prioritize variants based on expression findings from other projects and replicate our findings in independent samples. This project will also characterize the potential etiologic roles of reproducibly associated sarcoidosis risk variants by examining important smoking exposure and disease severity subgroups to determine whether disease risk depends on smoking history and/or whether these variants are associated with severity of lung involvement. The results of this study should provide important genes or regions for follow-up fine-mapping and functional studies that should ultimately provide better prevention and treatment targets for development.